Re-engineering gp120 to include glycan-dependent epitopes

重新设计 gp120 以包含聚糖依赖性表位

• 批准号: 8777908
• 负责人: Phillip Wayne Berman
• 金额: $ 202.62万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-18 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8777908
• 关键词: Africa; Antibodies; Antibody Affinity; Antibody Formation; Antigens; Attention; Basic Science; Binding; Biochemical; Biological Assay; Carbohydrates; Cell Culture System; Cell Line; Cells; Chinese Hamster Ovary Cell; Circular Dichroism; Clinical; Clinical Trials; Complex; Data; Development; Engineering; Ensure; Epitopes; Equipment; Follow-Up Studies; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Heterogeneity; Human; Immunization; Individual; Infection; Injecting drug user; Laboratory Animals; Mass Spectrum Analysis; Methods; Monoclonal Antibodies; Mus; National Institute of Allergy and Infectious Disease; Normal Cell; Oryctolagus cuniculus; Phase III Clinical Trials; Polysaccharides; Populations at Risk; Prevalence; Production; Proteins; Proteolysis; Protocols documentation; Qualifying; Recombinants; Recording of previous events; Regimen; Research; Resistance; Safety; Serum; Specificity; Structure; Subunit Vaccines; Testing; Thailand; Time; Unsafe Sex; Vaccine Antigen; Vaccine Research; Vaccines; Virus; Virus Diseases; Work; analytical method; blood product; carbohydrate structure; clinical material; cost; env Gene Products; experience; follow-up; glycosylation; immunogenicity; improved; injection drug use; kifunensine; manufacturing process; neutralizing antibody; nonhuman primate; novel; novel vaccines; pre-clinical; prevent; process optimization; public health relevance; scaffold; scale up; skills; stability testing; success; synthetic peptide; vaccine development

DESCRIPTION (provided by applicant): The goal of this work is the development of a safe, effective, and affordable vaccine to prevent HIV-1 infection resulting from injection drug use, unprotected sex, and exposure-contaminated blood products. We plan to accomplish this goal by improving a vaccine originally tested in injection drug users, AIDSVAX B/E. This proposal takes advantage of recent discoveries demonstrating that many of the most potent neutralizing antibodies in sera from HIV-1-infected people are directed to glycan-dependent epitopes. The recognition that broadly neutralizing antibodies recognize carbohydrate epitopes is revolutionary, and represents perhaps one of the greatest advances in the history of HIV-1 vaccine development. In this proposal, we plan to use this information to develop new vaccine immunogens consisting of recombinant gp120 and fragments of gp120 (scaffolds) produced with the glycosylation required for the binding of these antibodies. We plan to use these immunogens to improve the efficacy of the AIDSVAX B/E vaccine used in the RV144 and VAX003 clinical trials. Our recent studies showed that this vaccine lacked the carbohydrate structure required for the production of antibodies to this new and important class of epitopes. The key criteria of success in this proposal will be: 1) the identification of immunogens and an immunization regimen able to elicit broadly neutralizing antibodies in laboratory animals with activity similar to the prototypic PG9 monoclonal antibody, and 2) the identification of immunogens able to elicit antibodies to the V1/V2 domain of the type that correlated with protection in the RV144 trial. By improving an existing vaccine with an established record of safety and immunogenicity in more than 15,000 subjects, an existing GMP manufacturing process, and demonstrated efficacy, we believe that years of time and millions of dollars can be saved, compared with the cost of developing a new vaccine from scratch. Other useful information that will result from this proposal includes: 1) determining the best method to elicit antibodies to glycan-dependent epitopes in the V1/V2 domain of gp120; 2) the identification of new glycan-dependent and -independent epitopes in the V1 and V2 domains of gp120; 3) understanding the differences in the magnitude and specificity of antibody responses to V1/V2 domain that led to protection in the RV144 clinical trial and was unable to protect injection drug users in the VAX003 clinical trial, and 4) understanding the prevalence of antibodies to glycan dependent epitopes in people who make antibodies to gp120 as a consequence of immunization or virus infection.

描述（由申请人提供）：这项工作的目标是开发一种安全、有效和负担得起的疫苗，以预防因注射吸毒、无保护的性行为和接触受污染的血液制品而导致的HIV-1感染。我们计划通过改进最初在注射吸毒者中测试的疫苗AIDSVAX B/E来实现这一目标。这一建议利用了最近的发现，这些发现表明，hiv -1感染者血清中许多最有效的中和抗体是针对聚糖依赖性表位的。广泛中和抗体识别碳水化合物表位的认识是革命性的，可能是HIV-1疫苗开发历史上最伟大的进步之一。在本提案中，我们计划利用这些信息开发新的疫苗免疫原，由重组gp120和gp120片段（支架）组成，这些片段与这些抗体结合所需的糖基化产生。我们计划使用这些免疫原来提高RV144和VAX003临床试验中使用的AIDSVAX B/E疫苗的疗效。我们最近的研究表明，这种疫苗缺乏针对这类新的重要表位产生抗体所需的碳水化合物结构。该提案成功的关键标准将是：1)鉴定免疫原和免疫方案能够在实验动物中引发与原型PG9单克隆抗体活性相似的广泛中和抗体，以及2)鉴定免疫原能够引发与RV144试验中保护相关的类型的V1/V2结构域抗体。我们相信，与从头开始开发一种新疫苗的成本相比，通过改进现有疫苗，该疫苗已在超过15,000名受试者中建立了安全性和免疫原性记录，现有的GMP生产工艺，并证明了有效性，可以节省数年的时间和数百万美元。其他有用的信息包括：1)确定在gp120的V1/V2结构域中引出针对聚糖依赖性表位的抗体的最佳方法；2)在gp120的V1和V2结构域中发现新的葡聚糖依赖和葡聚糖独立的表位；3)了解在RV144临床试验中导致保护而在VAX003临床试验中无法保护注射吸毒者的V1/V2结构域抗体反应的幅度和特异性的差异，以及4)了解由于免疫或病毒感染而产生gp120抗体的人群中针对多糖依赖表位的抗体的患病率。